NF-κB Activation, Rather Than TNF, Mediates Hepatic Inflammation in a Murine Dietary Model of Steatohepatitis

作者: Aileen dela Peña , Isabelle Leclercq , Jacqueline Field , Jacob George , Brett Jones

DOI: 10.1053/J.GASTRO.2005.09.004

关键词:

摘要: Background& Aims: We explored the roles of nuclear factor-kappa B (NF-kappa B) and tumor necrosis factor (TNF) alpha (TNF-alpha) as mediators inflammation in a nutritional model steatohepatitis. Methods: Wild-type (wt), TNF null (-/-), receptor (R)-1-/- mice were fed methionine- choline-deficient (MCD) diet for up to 5 weeks. Liver injury (serum alanine aminotransferase [ALT]), hepatic inflammation, triglycerides, lipid peroxide levels determined. Hepatic NF-kappa activation expression intercellular adhesion molecule-1 (ICAM-1) assayed. Results: Irrespective genotype, MCD diet-fed developed peroxidation serum ALT elevation; at day 10, livers from wt, TNF-/-, TNFR-1-/- showed equivalent B/DNA binding was enhanced fractions wt compared with dietary controls; there corresponding increases ICAM-1 messenger RNA (mRNA). Likewise, by feeding TNF-/- respective controls. To establish whether is primary mediator experimental steatohepatitis, we overexpressed mutant, nondegradable I kappa (mI B), delivered adenovirus vivo. As expected, mI reduced induced feeding, resultant abrogation synthesis. Such blockade transcriptional substantially protected against development significant reductions liver inflammation. Conclusions: In activated early an important proinflammatory lesion development, but steatohepatitis occurs independently synthesis TNFR-1 activation.

参考文章(47)
Isabelle A. Leclercq, Geoffrey C. Farrell, Christine Sempoux, Aileen dela Peña, Yves Horsmans, Curcumin inhibits NF-κB activation and reduces the severity of experimental steatohepatitis in mice Journal of Hepatology. ,vol. 41, pp. 926- 934 ,(2004) , 10.1016/J.JHEP.2004.08.010
S. C. Lu, L. Alvarez, Z.-Z. Huang, L. Chen, W. An, F. J. Corrales, M. A. Avila, G. Kanel, J. M. Mato, Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation Proceedings of the National Academy of Sciences of the United States of America. ,vol. 98, pp. 5560- 5565 ,(2001) , 10.1073/PNAS.091016398
Michael D Wheeler, Hiroshi Kono, Ming Yin, Mikio Nakagami, Takehiko Uesugi, Gavin E Arteel, Erwin Gäbele, Ivan Rusyn, Shunhei Yamashina, Matthias Froh, Yuki Adachi, Yuji Iimuro, Blair U Bradford, Olivia M Smutney, Henry D Connor, Ronald P Mason, Sanna M Goyert, Jeff M Peters, Frank J Gonzalez, R Jude Samulski, Ronald G Thurman, The role of kupffer cell oxidant production in early ethanol-induced liver disease, Free Radical Biology and Medicine. ,vol. 31, pp. 1544- 1549 ,(2001) , 10.1016/S0891-5849(01)00748-1
P A Baeuerle, T Henkel, Function and Activation of NF-kappaB in the Immune System Annual Review of Immunology. ,vol. 12, pp. 141- 179 ,(1994) , 10.1146/ANNUREV.IY.12.040194.001041
Kenneth A. Roebuck, Alison Finnegan, Regulation of intercellular adhesion molecule-1 (CD54) gene expression. Journal of Leukocyte Biology. ,vol. 66, pp. 876- 888 ,(1999) , 10.1002/JLB.66.6.876
Arun J. Sanyal, Carol Campbell–Sargent, Faridoddin Mirshahi, William B. Rizzo, Melissa J. Contos, Richard K. Sterling, Velimir A. Luketic, Mitchell L. Shiffman, John N. Clore, Nonalcoholic Steatohepatitis: Association of Insulin Resistance and Mitochondrial Abnormalities Gastroenterology. ,vol. 120, pp. 1183- 1192 ,(2001) , 10.1053/GAST.2001.23256
Ming Yin, Michael D Wheeler, Hiroshi Kono, Blair U Bradford, Randle M Gallucci, Michael I Luster, Ronald G Thurman, None, Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice Gastroenterology. ,vol. 117, pp. 942- 952 ,(1999) , 10.1016/S0016-5085(99)70354-9
Isabelle A. Leclercq, Geoffrey C. Farrell, Jaqueline Field, David R. Bell, Frank J. Gonzalez, Graham R. Robertson, CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis Journal of Clinical Investigation. ,vol. 105, pp. 1067- 1075 ,(2000) , 10.1172/JCI8814
Hailing Liu, Brett E. Jones, Cynthia Bradham, Mark J. Czaja, Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α American Journal of Physiology-gastrointestinal and Liver Physiology. ,vol. 282, ,(2002) , 10.1152/AJPGI.00304.2001